NM_004004.6:c.-22-6T>C

Variant names:

• chr13-20189609-A-G
• rs141962118
• NM_004004.6:c.-22-6T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_004004.6(GJB2):​c.-22-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,596,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene GJB2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: GJB2 NM_004004.6 splice_region, intron
• Scores: Splicing: ADA: 0.0008351
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:9
• Conservation: PhyloP100: 0.0160
• Publications: 2 publications found

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

GJB2 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• syndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Specifications for GJB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 13-20189609-A-G is Benign according to our data. Variant chr13-20189609-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228700.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.-22-6T>C		splice_region intron	N/A	NP_003995.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.-22-6T>C		splice_region intron	N/A	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.-28T>C		5_prime_UTR	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.-28T>C		5_prime_UTR	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000494 AC: 123 AN: 248846 AF XY: 0.000511

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000944

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000747 AC: 1079 AN: 1444682 Hom.: 0 Cov.: 28 AF XY: 0.000736 AC XY: 530 AN XY: 719826

African (AFR) AF: 0.0000905 AC: 3 AN: 33136

American (AMR) AF: 0.000537 AC: 24 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85908

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5292

European-Non Finnish (NFE) AF: 0.000925 AC: 1015 AN: 1096792

Other (OTH) AF: 0.000569 AC: 34 AN: 59780

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74458

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.000784 AC: 12 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000578 Hom.: 0

Bravo AF: 0.000499

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	5	not provided (8)
-	2	-	Autosomal recessive nonsyndromic hearing loss 1A (2)
-	-	2	not specified (2)
-	1	-	Autosomal dominant nonsyndromic hearing loss 3A (1)
-	-	1	GJB2-related disorder (1)
-	-	1	Ichthyosis, hystrix-like, with hearing loss (1)
-	1	-	Nonsyndromic Deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		0.016
PromoterAI		-0.024	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00084
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 32
DS_AL_spliceai		0.37		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141962118; hg19: chr13-20763748;